The dosing of drugs is carried out in a number of different ways in the medical service today. For a number of reasons, such as local treatment of lung diseases, replacement of injection therapy and for rapid onset of action, there is a large interest in administering drugs to the lungs of a patient. A number of different devices have been developed in order to deliver drugs to the lung,; e.g. pressurized aerosols (pMDIs), nebulisers and dry powder inhalers (DPIs).
While inhalation of drugs already is well established for local treatment of lung diseases such as asthma, much research is going on to utilize the lung as a feasible entry into the body of systemically acting drugs. For locally acting drugs, the preferred deposition of the drug in the lung depends on the localization of the particular disorder and depositions in the upper as well as the lower airways are of interest. For systemic delivery of the medication, a deep lung deposition of the drug is preferred and usually necessary for maximum efficiency. With deep lung should be understood the peripheral lung and alveoli, where direct transport of active substance to the blood can take place.
The lung is an appealing site for systemic delivery of drugs as it offers a large surface area (about 100 m2) for the absorption of the molecules across a thin epithelium thereby giving potential for rapid drug absorption. Pulmonary delivery therefore has the advantage, compared to nasal delivery, that it is possible to obtain a sufficiently high absorption without the need of enhancers. The feasibility of this route of administration is for a particular drug depends on, for example, dose size and extent of absorption for the particular substance.
The critical factors for the deposition of inhaled particles in the lung are inspiration/expiration pattern and the particle aerodynamic size distribution. For maximum lung deposition, the inspiration must take place in a calm manner to decrease air speed and thereby reduce deposition by impaction in the upper respiratory tracts.
For dry powder inhalers there are restrictions on the aerodynamic particle size of the drug particles to obtain an acceptable deposition of the drug within the lung. If a particle is to reach into the deep lung the aerodynamic particle size should typically be less than 3 μm, and for a local lung deposition, typically about 5 μm. Larger particle sizes will easily stick in the mouth and throat. Thus, regardless of whether the objective is a local or systemic delivery of a drug, it is important to keep the aerodynamic particle size distribution of the dose within tight limits to ensure that a high percentage of the dose is actually deposited where it will be most effective.
De-Aggregation
Powders with a particle size suitable for inhalation therapy have a tendency of aggregating, in other words to form smaller or larger aggregates, which then have to be de-aggregated before the particles enter into the airways of the user. De-aggregation is defined as breaking up aggregated powder by introducing energy e.g. electrical, mechanical, pneumatic or aerodynamic energy. Some dry powder inhalers rely on external sources of de-aggregating power e.g. mechanical, electrical or pneumatic, yet some rely only on the power provided by the user's inspiration.
The aerodynamic particle diameter is the diameter of a spherical particle having a density of 1 g/cm3 that has the same inertial properties in air as the particle of interest. This means that the aerodynamic particle size is determined by the primary particle size, the shape of the particle and the particle density. If primary particles are incompletely de-aggregated in the air, the aggregate will aerodynamically behave like one big particle. Hence, for a particular drug substance there are three major, principally different ways to vary the aerodynamic particle size distribution from a dry powder inhaler, DPI, by a) varying the primary particle size distribution or b) by varying the degree of de-aggregation or c) by varying the particle density (making a particle look like tumbleweed).
Current inhalation devices, intended for asthma and other lung diseases, normally deliver the aerosolized drug in an aerodynamic size range suitable for local lung deposition. This aerodynamic particle size distribution is often caused by an inefficient de-aggregation of powder with a primary particle size in the range 2-3 μm. Thus, the inhaled dose largely consists of aggregates of particles. This has several disadvantages, the most important being:                The uniformity of aerodynamic particle size distribution between different doses may vary considerably, because the de-aggregation is sensitive to slight differences in inspiration conditions from one inhalation to the next.        Particle size distribution of the delivered dose may have a tail of large aggregates, which will deposit in the mouth and upper airways.        
A better, more robust situation is obtained with a high degree of de-aggregation of the medication powder in the inhaled air as a good de-aggregation gives a better repeatability and efficiency of drug deposition in the lung. Preferably, the de-aggregating system should be as insensitive as possible to the inhalation effort produced by the user, such that the delivered aerodynamic particle size distribution in the inhaled air is independent of the inhalation effort.
Hence, for an efficient delivery of drugs to the lung there is a need for a system consistently generating a very high degree of de-aggregation of the medication powder when the patient inhalation effort is varied within reasonable limits. This is obvious for systemically acting drugs where a deep lung deposition is needed, but also for locally acting drugs, where a more local lung deposition is preferred, a consistent high degree of de-aggregation of the medication powder is advantageous. In this way the aerodynamic particle size distribution will be less dependent upon the users inhalation effort. The average particle size, which influences the deposition pattern in the lung, can be controlled by the primary particle size distribution of the particles in the powder. Larger primary particle size and excellent de-aggregation offers a robust system for local lung delivery.
A very high degree of de-aggregation presumes the following necessary steps:                a suitable formulation of the powder (particle size distribution, particle shape, adhesive forces, density, etc.)        a suitably formed dose of the powder adapted to the capabilities of a selected inhaler device        an inhaler device providing shear forces of sufficient strength in the dose to de-aggregate the powder (e.g. turbulence, impaction)        
Turning to the drug formulation, there are a number of well-known techniques to obtain a suitable primary particle size distribution to ensure the potential for a correct lung deposition for a high percentage of the dose. Such techniques include jet-milling, spray-drying and super-critical crystallization.
There are also a number of well-known techniques to modify the forces between the particles and in such way obtaining a powder with suitable adhesive forces. Such methods include modification of the particles shape and surface properties of the particles, e.g. porous particles and controlled forming of powder pellets, as well as addition of inert carrier with a larger average particle size (so called ordered mixture).
Most locally acting drugs for inhalation presently on the market are rather small organic molecules. Examples of employed drugs include steroids such as budesonide, broncodilators such as salbutamol and similar substances.
For many of these drug substances, the pharmaceutical formulation development work is rather straightforward. On the other hand, novel drugs both for local and systemic delivery often includes biological macromolecules with completely new demands on the formulation.
A number of proteins and peptides have a potential for being suitable for inhalation therapy and some of them are in various stages of development. Some examples are insulin, alpha-1-proteinase inhibitor, interleukin 1, parathyroid hormone, genotropin, colony stimulating factors, erythropoietin, interferons, calcitonin, factor VIII, alpha-1-antitrypsin, follicle stimulating hormones, LHRH agonist and IGF-I.
Protein and peptide drugs (PPDs) have characteristics that present significant formulation challenges. In particular their chemical and enzymatic lability practically prevents traditional dosage forms such as oral tablets. Therefore PPDs are currently mainly administered parenterally as intravenous, intramuscular or subcutaneous injections. While these routes are normally satisfactory for a limited number of administrations, there are problems with a long-term therapy. Frequent injections, necessary for the management of a disease, is of course not an ideal method of drug delivery and often leads to a low patient compliance as they infringe on the freedom of the patient. Further, many patients are reluctant to inject for psychological reasons and therefore inject with larger time intervals than what is medically desirable.
Insulin is an example of an important peptide drug where frequent parenteral administrations are the most common way of administration. A large percentage, perhaps 5%, of the human population suffers from Diabetes Mellitus. Diabetes is caused by impaired or insufficient insulin production. Normally the blood glucose level is continuously controlled by the natural insulin production of the body, but when this does not happen in the case of diabetes, the glucose concentration may rise to high and maybe life-threatening levels. In such cases insulin in suitable quantities must be externally supplied for management of the disease.
Self-administration of insulin is an important reality and part of everyday life for many patients with diabetes. Normally, the patient needs to administer insulin several times daily. Insulin given orally has not been effective because insulin is degraded in the gastrointestinal tract resulting in systemic concentrations too low for therapeutic effect.
The most common method of insulin administration is subcutaneous injection by the patient based on close monitoring of the glucose level. As mentioned above, frequent injections are not an ideal method of drug delivery. Further, there are pharmacokinetical limitations when using the subcutaneous route. Absorption of insulin after a subcutaneous injection is rather slow. It sometimes takes up to an hour before the glucose level in the blood begins to be significantly reduced. This inherent problem with subcutaneous insulin delivery cannot be solved with a more frequent administration. To obtain plasma insulin concentrations that are physiologically correct it is necessary to choose another route of administration.
Delivery of protein and peptide drugs (PPDs) through nasal passage generally gives a rather low and variable bioavailability. Factors affecting the bioavailability from the nasal cavity include the limited surface area (approximately 150 cm2), the large molecular size of the PPDs, mucocilliary clearance and enzymatic degradation. With the help of absorption enhancing agents the absorption of PPDs from the nasal cavity can be significantly improved. A rather large number of enhancers have been tested and suggested mechanisms are that they open the tight junctions, disrupt membrane or inhibits enzymes. However, penetration enhancers often cause local irritation on the nasal membrane, a problem that has proved difficult to solve.
Delivery by inhalation of aerosolized insulin is documented as far back as in the 1920's (M. Gänsslen “Über Inhalation von Insulin”). The natural state for insulin as a medical substance is still in solution-form, so that historically from the 1920's onwards research into nasal and pulmonary administration of insulin has been concentrated to various liquid formulations of insulin.
Methods to manufacture dry powder insulin from a liquid state has been known and applied for more than 50 years, including such methods as evaporation, spray-drying and freeze-drying. However, reliable and economic technologies have been lacking for on one hand producing insulin powders with suitable properties and on the other hand suitable apparatuses for delivering the powder to the user in a way that ensures an effective systemic delivery. This has prevented the main-stream research from using insulin in dry powder formulations. However, in the early 1990's Bäckström, Dahlbäck, Edman and Johansson (Therapeutic preparation for inhalation WO 95/00127) showed that inhalation of a therapeutic preparation comprising insulin and an absorption enhancer quickly and efficiently leads to insulin being absorbed in the lower respiratory tract. It is evident that the enhancer was necessary probably because of insufficient de-aggregation of the powder and the use of an inferior dry powder inhaler. During the last decade a number of reports describing the pharmacokinetics and pharmacodynamics of insulin delivered to the lung of humans have been published. In most reported cases, the insulin has been nebulised from an aqueous preparation. However, in the early 1990's some research into the effect of pulmonary administration of insulin in dry powder form was performed. It has been demonstrated that systemic delivery of dry insulin powder can be accomplished by oral inhalation and that the powder can be rapidly absorbed through the alveolar regions of the lung. For instance, in U.S. Pat. No. 5,997,848 it is demonstrated that systemic delivery of dry insulin powder is achieved by oral inhalation and that the powder can be rapidly absorbed through the alveolar regions of the lungs. However, dose resolution still seems to be low. According to the disclosure, the insulin dosages are having a total weight from a lowest value of 0.5 mg up to 10-15 mg of insulin and the insulin is present in the individual particles at from only 5% up to 99% by weight with an average size of the particles below 10 μm.
A number of factors make delivery of PPDs to the lung as dry powders an attractive option. PPDs are susceptible to several paths of degradation including deamidation, hydrolysis and oxidations. Therefore, an acceptable stability of the pharmaceutical product can be a difficult task in many cases. From a stability point of view, a solid formulation stored under dry conditions is normally the best choice. In the solid state, these molecules are normally relatively stable in the absence of moisture or elevated temperatures. Proteins and peptides of moderate molecular weights are soluble in the fluid layer in the deep lung and dissolve therefore ensuring rapid absorption from the lung.
Turning to the presentation of the dose, two main classes of dry powder systems are available on the market, the reservoir type where the powder is present in the inhaler as a bulk, and the single dose type where the powder is pre-metered into single doses. In the first case, the dose is metered off by the patient using the device, while in the second case the dose has been metered off and enclosed into for example gelatin capsules or Al-blister by the manufacturer.
A special case of pre-metered doses is the electrostatically or electro-dynamically manufactured doses, see our U.S. Pat. No. 6,089,227 and our Swedish Patents SE 9802648-7, SE 9802649-5 and SE 0003082-5. See also U.S. Pat. Nos. 6,063,194, 5,714,007, 6,007,630 and the International Application WO 00/22722. The contour of a dose manufactured in this way can be tailored to suit a particular application. In addition, there are also large opportunities to tailor the internal powder structure, such as porosity, which will influence the adhesion forces between the particles.
A large number of different concepts to de-aggregate the drug powder in DPIs have been developed. One example is the use of a spacer, which is based upon having the aerosolized particles distributed evenly in a container from which the inhalation can take place. In principle an inhaler is coupled to a container having a relatively large volume and into which a powder aerosol is injected. Upon inhalation from the spacer the aerosolized powder will effectively reach the alveoli. This method in principle has two drawbacks, firstly difficulties to control the amount of medicine emitted to the lung as an uncontrolled amount of powder sticks to the walls of the spacer and secondly difficulties in handling the relatively space demanding apparatus.
External sources of energy to amplify the inhalation energy provided by the user during the act of inhalation are common methods in prior art inhalers for improving the performance in terms of de-aggregation. Some manufacturers utilize electrically driven propellers, piezo-vibrators and/or mechanical vibration to de-aggregate the agglomerates. The addition of external sources of energy leads to more complex and expensive inhalers than necessary, besides increasing the demands put on the user in maintaining the inhaler.
Hence, there is a demand for suitable therapeutic preparations of medication substances and a method and for providing a highly effective de-aggregation and dispersal into air of a medication powder in connection with administration to a user inhaling through a new type of inhaler device.